Antibodies to IL-6 and use thereof

• US 7,935,340 B2
• Filed: 05/21/2008
• Issued: 05/03/2011
• Est. Priority Date: 05/21/2007
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: AlderBio Holdings, LLC (Lundbeck Seattle Biopharmaceuticals, Inc.)
• Inventors: Jensen, Anne Elisabeth Carvalho, Garcia-Martinez, Leon, Kovacevich, Brian, Dutzar, Ben, Olson, Katie, Ojala, Ethan, Smith, Jeffrey T. L., Latham, John
• Primary Examiner(s): Spector; Lorraine
• Application Number:
  US12/153,612
• Publication Number:
  US 20090028784A1
• Time in Patent Office: 1,077 Days
• Field of Search: None
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 16/248 : IL-6
• CPC Class Codes: C07K 2317/20 : characterized by taxonomic origin
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/41 : Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention is directed to antibodies and fragments thereof having binding specificity for IL-6. Another embodiment of this invention relates to the antibodies described herein, and binding fragments thereof, comprising the sequences of the V_H, V_L and CDR polypeptides described herein, and the polynucleotides encoding them. The invention also contemplates conjugates of anti-IL-6 antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention also contemplates methods of making said anti-IL-6 antibodies and binding fragments thereof. Embodiments of the invention also pertain to the use of anti-IL-6 antibodies, and binding fragments thereof, for the diagnosis, assessment and treatment of diseases and disorders associated with IL-6. These antibodies may bind at least one of soluble IL-6, cell surface expressed IL-6, IL-6/IL-6R and/or prevent the association of IL-6 and IL-6R, the association of IL-6/IL-6R and gp130 and or the formation of IL-6/IL-6R/gp130 multimers and thereby inhibit a biological effect associated with any of the foregoing.

Claims

1. An anti-human IL-6 antibody or antibody fragment comprising a variable light chain comprising the CDR 1 sequence of SEQ ID NO:

4, the CDR 2 sequence of SEQ ID NO;

5, and the CDR 3 sequence of SEQ ID NO;

6, and a variable heavy chain comprising the CDR 1 sequence of SEQ ID NO;

7, the CDR 2 sequence of SEQ ID NO;

8 or SEQ ID NO;

120, and the CDR 3 sequence of SEQ ID NO;

9.

4. An anti-human IL-6 antibody or antibody fragment that comprises the CDRs in an anti-human IL-6 antibody according to claim 1 or 2 wherein the variable heavy and light chains are each at least 90% identical to the variable heavy and light chains in SEQ ID NO:

19 and 20 respectively.

5. An anti-human IL-6 antibody or antibody fragment according to claim 1 that is selected from the group consisting of chimeric, humanized, and human antibodies or antibody fragments.

6. An anti-human IL-6 antibody or antibody fragment according to claim 1 that is selected from the group consisting of scFvs, camelbodies, nanobodies, IgNAR (single-chain antibodies derived from sharks) and F_ab , F_ab′

or F<sub>(ab′

)2</sub> fragments.

7. An anti-human IL-6 antibody or antibody fragment according to claim 1, 2 or 3 that is non-glycosylated.

8. An anti-human IL-6 antibody or antibody fragment according to claim 1, 2 or 3 that comprises a human constant domain.

9. An anti-human IL-6 antibody or antibody fragment according to claim 8 that is an IgG1, IgG2, IgG3or IgG4antibody.

10. An anti-human IL-6 antibody or antibody fragment according to claim 1, 2 or 3 which contains an Fc region that has been modified to alter at least one of effector function, half-life, proteolysis, or glycosylation.

11. The anti-human IL-6 antibody or antibody fragment of claim 10 wherein the Fc region contains a mutation that alters or eliminates glycosylation.

12. An anti-human IL-6 antibody or antibody fragment according to claim 1, 2 or 3 which is a humanized antibody or antibody fragment.

13. An anti-human IL-6 antibody or antibody fragment according to claim 1, 2 or 3 which is directly or indirectly attached to a detectable label or therapeutic agent.

14. An anti-human IL-6 antibody or antibody fragment according to claim 1, wherein said antibody binds to IL-6 with a dissociation constant (K_D) of less than or equal to 5×

10<sup>−

10</sup>.

15. An anti-human IL-6 antibody or antibody fragment according to claim 1, 2 or 3 which further comprises an effector moiety.

16. The anti-human IL-6 antibody or antibody fragment of claim 15, wherein the effector moiety is a detectable moiety or a functional moiety.

17. The antibody or antibody fragment of claim 16 wherein said detectable moiety is a fluorescent dye, an enzyme, a substrate, a bioluminescent material, a radioactive material, or a chemiluminescent material.

18. The antibody or antibody fragment of claim 16, wherein said functional moiety is streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, or a radioactive material.

19. An anti-IL-6 antibody or antibody fragment according to claim 4, wherein said antibody comprises a variable light or heavy chain which respectively are at least 95% identical to the variable light or variable heavy chain polypeptides contained in SEQ ID NOs:

20 and 19.

20. A anti-IL-6 antibody or antibody fragment according to claim 4 wherein said antibody or antibody fragment comprises a variable light or heavy chain which is at least 98% identical to the variable light or variable heavy chain polypeptides respectively contained in SEQ ID NOs:

20 and 19.

21. An isolated anti-IL-6 antibody or antibody fragment according to claim 4, wherein said antibody or antibody fragment comprises a variable light or heavy chain which is at least 99% identical to the variable light or variable heavy chain polypeptides respectively contained in SEQ ID NOs:

20 and 19.

22. A composition containing an anti-human IL-6 antibody or antibody fragment according to claim 1, 2 or 3 and a carrier or excipient.

23. The composition of claim 22 that is suitable for therapeutic or diagnostic use.

24. The composition of claim 23 which further comprises at least one stabilizer.

26. The anti-IL-6 antibody or antibody fragment of claims 1 which comprises human IgG1constant domains.

2. An anti-human IL-6 antibody or antibody fragment comprising the variable heavy chain in SEQ ID NO:

2, 18 or 19 and the variable light chain contained in SEQ ID NO;

3 or 20.

3. An anti-human IL-6 antibody or antibody fragment which comprises the variable heavy chain in SEQ ID NO:

19 and the variable light chain contained in SEQ ID NO;

20.

27. The anti-IL-6 antibody or antibody fragment of claims 3 which comprises human IgG1 constant domains.

25. An anti-human IL-6 antibody or antibody fragment which comprises the variable heavy chain in SEQ ID NO:

18 and the variable light chain contained in SEQ ID NO;

20.

28. The anti-IL-6 antibody or antibody fragment of claims 25 which comprises human IgG1constant domains.